The Hallmarks of Cancer

In 2000, the first hallmarks of cancer were published. There were 6 behaviors all cancers would develop as they go from healthy cells to metastatic growth. This was the first attempt to organize the complexity of cancer biology. Since then, we have added four more. Cancer begins when a cell loses control over the functions that regulate cell growth. It begins with genetic instability, loss of mortality, uncontrolled growth and loss of growth inhibitors. These are the main genetic drivers of cancer. Then it proceeds to immune invasion by learning to escape immune detection and promoting an environment of tolerance. There are a few other hallmarks of cancer that transition into invasion, angiogenesis, and metastasis.

Hallmark 1: Sustained Proliferative Signaling

The first hallmark of cancer is sustained growth signaling. Under normal circumstances, the cells of the body do not replicate unless it is necessary. Some cells will normally replicate frequently and others will never replicate. Cancer begins when a cell begins to act on its own replicating without the necessary signaling. This can happen when a mutation occurs in one of the growth pathways. These are those proto-oncogenes that mutate to become oncogenes which drives cell proliferation. They are mutations in the growth receptors for growth signals like EGFR, VEGF, FGFR and PDGF and many more. These types of mutations will lead to an always on state for those growth factor receptors. This is called becoming Constitutively Active.

Some of these increased growth signals come from the duplication of a gene during DNA synthesis. This leads to multiple copies of a growth receptor. This leads to hyperactivity of the cell from an over expression of growth receptors. These are called amplification mutations. Some of these proto-oncogene mutations occur in the internal cellular growth pathways like RAS, RAF, MEK, ERK, PI3K and AKT. These pathways link the growth receptors to the genes in the cell that control growth. It only takes one mutation in one of these oncogenes to drive increased cell growth. These cells can be perfectly normal in every way except they are replicating at a faster rate. Mutations in proto-oncogenes lead to gain of function mutations.

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Hallmark 2: Evading Growth Suppressors

The second hallmark of cancer is the loss of those genes that prevent cells from growing without the proper signals. They involve proteins that verify the DNA during the cell cycle checkpoints like p53, p21 and Rb. These genes regulate the cell cycle by blocking growth under normal conditions are called Tumor Suppressor genes. They act like the brakes for the cell growth cycle. Mutations in the Tumor Suppressor genes cause a loss of function. They include the DNA Damage Repair (DDR) pathway proteins and enzymes that fix damage to the DNA. DNA damage repair pathways fix damage from stress like oxidation, radiation and chemicals. These tumor suppressor genes are broken down into gatekeeper genes and caretaker genes. The gatekeepers are those genes that act as the breaks to cell replication. They are there to prevent it from occurring unless the proper signals have been given. The caretaker genes are there to ensure the integrity and control DNA repair.

Since there are 2 copies of every Tumor Suppressor gene, they will still work if only 1 gene is lost. This leads us to the 2 hit hypothesis of tumor suppressor genes. This states that both genes must be lost before the function of a tumor suppressor gene is completely lost.

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Hallmark 3: Genomic Instability

This hallmark is considered one of the first mutations to occur. Genetic Instability makes the cell unstable and allows for the rapid and progressive mutations from one generation to the next. This occurs when the cell loses the ability to quality check its DNA when it replicates like the p53 protein or DNA repair proteins. We said that a cell makes about one mistake in copying the DNA each time it replicates the DNA. Most of them are caught and corrected. Genetic Instability occurs when something mutates to stop this quality check or the DNA Damage Repair pathways.

Some of the genetic instability leads to errors in the actual chromosomes like gene deletions, duplications and translocations. These are called gene rearrangements and they alter the DNA. Many of these errors are common to specific types of cancer. One such example is the Philadelphia Chromosome. It's a translocation between Chromosome 9 and 22. A portion of each chromosome is cut and placed on the opposite chromosome. One such concept is called chromothripsis where the chromosomes gain many of these rearrangement mutations This becomes like the scrambling of the chromosome with many mutations.

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Hallmark 4: Resist Death Signals

The next hallmark is the shifting of the balance between the signals that tell a cell to survive over those that tell it to die. All cells are constantly getting feedback in the form of signals that tell them when they should survive and when they should die. You want a healthy cell to survive and bad cells to die. Only when something goes wrong, should it initiate programmed cell death (Apoptosis). In cancer, the pathways for the survival signals will mutate and greatly shift that balance in favor of survival even in conditions where a cell should undergo death like DNA damage.

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Hallmark 5: Replicative Immortality

Telomeres are the caps on the end of each chromosome. Think of them like the little caps on the end of your shoe strings. They have a specific length. Each time a cell replicates, the telomere gets slightly shorter. After several generations of replication, you can exhaust the telomere. After the telomere runs out, the cell can no longer replicate. This is called the Hayflick limit. It is called Senescence when the cell reaches its limitations to replication. The stem cells are immortal as they have a gene active for them to extend their telomeres each time they replicate. Cancer cells mutate to turn on the telomerase enzyme which extends the telomeres after each replication giving them attributes of stem cells. This gives them immortality.

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Hallmark 6: Reprogramming Metabolism

Cancer cells will mutate their ability to take up glucose to power their rapid replication. It is shown that Cancer cells will uptake glucose at 100x the rate of normal cells. Since the tumor usually forms in the tissue where there is no or little oxygen, cancer cells will often rewire their metabolism to make them anaerobic. The cellular respiration cycle has several processes of glycolysis, the Krebs cycle and the Electron Transport Chain. The later two use oxygen to break down glucose and make ATP which the cell uses for energy. The process of Glycolysis does not require oxygen which allows cancer cells to use this part of the process to produce energy for survival in a low oxygen environment of the tissue. This takes the glucose and breaks it down into Lactic Acid instead of Pyruvate which gets used in the rest of the process. This leaves the tumor microenvironment very acidic.

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Hallmark 7: Angiogenesis

The next hallmark of cancer is the creation of new blood vessels. This is also the first step toward metastasis. The blood vessels provide a connection for the tumor to the circulation and the rest of the body. Tumors need a lot of nutrients to drive their growth. They will release Vascular Endothelial Growth Factor (VEGF) which will act on the endothelial cells of nearby blood vessels. This will cause them to create new routes of blood vessels toward those signals. Angiogenesis of new vessels act as a boost for the tumor. It provides key nutrients to the tumor to promote growth, and it acts as a highway system for tumor cells to move into the circulation and travel to other tissues.

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Hallmark 8: Tumor Promoting Inflammation

The tumor will hijack the inflammation process and use it to promote its own growth. The tumor promotes NF-kappa signaling of immune cells which release inflammatory signals to recruit immune cells to the tumor microenvironment. The tumor will release signals to recruit neutrophils which can degranulate and damage nearby healthy cells, clearing the way for the tumor to expand and grow. The helper T cells and macrophages in the area can also release growth signals which help drive the growth of tumor cells. The tumor not only learns to avoid the immune system, but it uses the immune system to do its bidding.

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Hallmark 9: Avoiding Immune Destruction

Tumor cells must learn to evade immune destruction. The immune system is designed to find and kill mutated cells. The tumor can develop many mechanisms by which it will block the immune response. The first is that the tumor will promote the creation of T regulatory cells. It does this by secreting cytokines like IL-10 and TGF-beta. This will cause T helper cells to switch into induced T regs. They will then release cytokines which will shut down the immune response toward the tumor. The macrophages in the area will be switched away from the M1 phenotype which kills tumor cells and to the M2 phenotype so they release TGF-beta which promotes growth for the tumor and inducement of T regulatory cells. The tumor cells can express ligands on their surface that can deactivate cytotoxic T cells and Macrophages. They can express PD-L1 which will stop cytotoxic T cells from killing them. The constant activation of these T cells without the ability to kill leads to them becoming exhausted, causing them to fail to respond at all. The tumor cells can also express CD47 which will prevent any M1 macrophages from killing them.

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Hallmark 10: Invasion and Metastasis

The last Hallmark for cancer is the ability to invade nearby tissue and travel to distant tissues and set up secondary tumors. Normally, cells are anchored to where they belong by cell adhesion molecules. They hold the cell in place. A mutation in these cellular adhesion molecules will allow the cells to break free from their normal tissue and invade nearby tissue. If there are blood vessels nearby, they can also travel through the blood to distant sites and spread. This process is called metastasizing. The statistics show that 90% of cancers become fatal once they are metastatic. During the process of metastasis, the cells must undergo a transition from a normal Epithelial cell into a Mesenchymal type stem cell. This process is called the Epithelial to Mesenchymal Transition (EMT). The Mesenchymal cell is a stem cell-like population. These invasive EMT cells will intravasate into the blood vessels where they become circulating tumor cells (CTCs). The circulation is very hostile to these CTC cells, but survivors can extravasate into new tissues called homing.

Certain cancers like to home to specific tissues when it comes to creating metastasis called Mets. This brings us to the seed and soil hypothesis. This states the CTC cells are like seeds that spread out from the tumor. They will spread everywhere, but they will only be able to take root in congenial soil that will support new growth. Some of these EMT cells can lay dormant for decades at new sites before they start to grow a new metastasis. Each cancer type will have specific tissues where it tends to spread like prostate cancer nearly always goes to the bone. The most common place metastases appear are Brain, Bone, Liver and Lungs.

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